Intracellular receptors are a class of structurally related proteins involved in the regulation of gene transcription. Steroid receptors are a subset of these receptors, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Regulation of a gene requires the intracellular receptor and a corresponding ligand which has the ability to selectively bind to the receptor in a way that affects gene transcription.
Progesterone receptor modulators (progestagens and antiprogestagens) are known to play an important role in the health of women. The natural ligand for PR is the steroid hormone progesterone, but synthetic compounds have been made which may also serve as ligands (see e.g. Jones et al U.S. Pat. No. 5,688,810).
Progestagens are currently widely used for hormonal contraception and in HRT. Other important clinical applications of progestagens are treatment of gynaecological disorders (e.g. endometriosis, dysmenorrhea, dysfunctional uterine bleeding, severe premenstrual syndrome), breast cancer, hot flushes and mood disorders, and luteal support during IVF. In addition, they are applied in combination with other hormones and/or other therapies including, without limitation, chemotherapeutic agents such as cytotoxic and cytostatic agents, immunological modifiers such as interferons and interleukins, growth hormones or other cytokines, hormone therapies, surgery and radiation therapy.
The current steroidal progestagens have been proven to be quite safe and are well tolerated. Sometimes, however, side effects (e.g. breast tenderness, headaches, depression, and weight gain) have been reported that are attributed to these steroidal progestagens, either alone or in combination with estrogenic compounds. In addition, steroidal ligands for one receptor often show cross-reactivity with other steroidal receptors. Many progestagens also bind e.g. to the androgen receptor, whereas many antiprogestagens have affinity for the glucocorticoid receptor.
Antiprogestagens in combination with progestagens are also useful in contraceptive and hormone replacement regimens as described e.g. in WO 99/25360 and WO 97/49407. It would therefore be useful to find compounds which have both progestagenic and antiprogestagenic properties within one molecule.
WO 99/45022 describes 20-keto-11β-arylsteroids which have either antagonistic or agonistic activity towards the progesterone receptor. Of the many compounds disclosed in WO 99/45022, three or four compounds have both progesterone antagonist and agonist activity. None of these compounds has a substituent in position 16; in position 17α, they have an acetyloxy, acetyloxymethyl or methoxymethyl substituent.
The compounds described in EP 349481 contain a 4-[(3-pyridyl)phenyl] substituent in position 11β and have no substituent in position 16; none of these compounds possesses a cyclopropylcarbonyl or cyclopropenylcarbonyl substituent in position 17, nor a spirocycloalkanone or spirocycloalkenone substituent in position 17. The compounds of EP 349481 have antiprogestagenic properties only.
The subject invention now surprisingly discloses that novel steroid compounds with an (11β)-[4-(aza-aryl)phenyl] substituent in combination with a variety of substituents in positions 16 and 17 show a mixed profile of PR agonist and PR antagonist activity (hereinafter referred to as mixed P/AP profile) within one compound. These compounds are particularly useful for contraction, HRT and the treatment of gynaecological disorders. Cook et al. (Life Sciences 52 (1993), 155-162) describes the possibility that a steroid which has an antiprogestagenic profile with an acetyloxy substituent at the 17α position can be turned into a compound with a mixed profile by deleting this substituent, while introduction of a substituent in the 16α position turns the compound into a full agonist Surprisingly, this is not the case for the novel compounds disclosed in the subject invention, which uniformly have mixed profiles with various combinations (including hydrogen) of 16α- and 17α-substituents.